Loss of vision not only alters the function of the brain processing visual information, but also affects the function of other sensory systems. This type of "cross-modal" plasticity has been observed in blind humans, and is thought to provide a compensatory mechanism to better utilize the remaining sensory modalities in the absence of vision. While the cross-modal changes are beneficial to blind individuals, they pose a challenge when devising clinical interventions to overcome the loss of vision because extensive cross-modal changes in neural circuitry may hinder restoration of normal function. So far most research has focused on the systems level analyses of cross-modal changes, however, the cellular and molecular mechanisms have not been explored. The long-term objective of this application is to understand the cellular and molecular mechanisms underlying cortical plasticity following changes in visual experience. Recently we found that depriving vision (by dark-rearing) of rodents not only increases excitatory synaptic transmission in the superficial layers of the visual cortex, but also produces opposite changes in other primary sensory cortices. These changes followed the rules of a homeostatic plasticity mechanism, which provides stability to neural networks following prolonged perturbation in neural activity. These changes were accompanied by correlative changes in AMPA receptor subunit composition at synapses. We hypothesize that the homeostatic plasticity observed cross-modally in other sensory cortices by visual deprivation may be a cellular correlate of cross-modal plasticity observed in blind individuals. Interestingly, the homeostatic changes in the function of visual cortex, as well as other sensory cortices, by visual deprivation occurred quite rapidly (within a week) and were readily reversed by restoring vision (by re-exposing the animals to a lighted environment). In this proposal we will determine the cellular mechanisms and functions of global homeostatic cross-modal plasticity in primary sensory cortices. Specifically, we aim to investigate visual experience-induced global homeostatic plasticity in terms of its (1) induction mechanisms, (2) molecular mechanisms, and (3) functional consequences at a cortical circuit level. To do this, we will combine electrophysiological measure of excitatory synaptic transmission using whole-cell patch clamp techniques, biochemical and immunohistochemical analyses of synaptic proteins, and utilize various genetically altered mice and in vivo gene knockdown. Results from the proposed experiments will provide insights into developing better treatment options for various visual deficits, which may differ depending on the degree of vision affected and the extent of cross-modal changes elicited. PUBLIC HEALTH RELEVANCE It is known that blind individuals display a compensatory enhancement in the remaining sensations when compared to normal sighted individuals. These changes, termed "cross-modal plasticity", while beneficial to the blind individual, poses a challenge in developing effective treatments for vision loss because extensive cross-modal changes hinder restoration of normal function. Knowledge gained from our work will provide insights into developing better therapies for various forms of visual deficits, which may require distinct treatment options depending on the degree of vision affected and the extent of cross-modal changes elicited.